Pharmacogenetic Pathway Analysis of Docetaxel Elimination
Pharmacogenetic Pathway Analysis of Docetaxel Elimination
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DOI：
10.1038/clpt.2008.95
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发表时间：
2009-02-01
影响因子：
6.7
通讯作者：
Sparreboom, A.
中科院分区：
文献类型：
--
作者：
Baker, S. D.;Verweij, J.;Sparreboom, A.
本研究的目的是评估多西他赛对14种转运蛋白的亲和力，并评估参与药物消除的5个基因中17种变体的功能意义。在研究的转染模型中，OATP 1B 3（SLCO 1B 3）被鉴定为多西他赛最有效的流入转运蛋白。在92例白色患者中，观察到的基因型（SLCO 1B 3、ABCB 1和ABCC 2）均与多西他赛清除率无关（P > 0.17）。然而，同时存在CYP 3A 4 *1B和CYP 3A 5 *1A等位基因与多西他赛清除率增加64%相关（P = 0.0015），与性别和CYP 3A活性无关（通过红霉素呼气试验测定）。该单倍型也与另一人群中咪达唑仑清除率增加相关（P = 0.0198）。对CEPH-HapMap样本中CYP 3A基因座的分析揭示，CYP 3A 4 *1B仅存在于CYP 3A 5表达子的子集中。因此，未来的研究应该首先根据CYP 3A 5基因型对人群进行分层，然后比较有和没有CYP 3A 4 *1B等位基因的个体之间的CYP 3A活性。
The purpose of this study was to evaluate the affinity of docetaxel for 14 transporter proteins and assess the functional significance of 17 variants in five genes involved in drug elimination. among the transfected models investigated, OATP1B3 (SLCO1B3) was identified as the most efficient influx transporter for docetaxel. none of the observed genotypes (SLCO1B3, ABCB1, and ABCC2) was related with docetaxel clearance in 92 white patients (P > 0.17). however, the simultaneous presence of the CYP3A4*1B and CYP3A5*1A alleles was associated with a 64% increase in docetaxel clearance (P = 0.0015), independent of both sex and CYP3A activity (as determined using the erythromycin breath test). This haplotype was also associated with increased midazolam clearance in another population (P = 0.0198). an analysis of the CYP3A locus among CEPH-HapMap samples revealed that CYP3A4*1B is present exclusively among a subset of CYP3A5 expressors. Therefore, future studies should first stratify the population on the basis of CYP3A5 genotype and then compare CYP3A activity between individuals with and without the CYP3A4*1B allele.